Why resist insulin?

Finding genes associated with insulin resistance

Researchers have uncovered six genetic regions that appear to affect resistance to the effects of insulin, which is
important in many cases of type 2 diabetes. Previously, only two regions had been described.

The team were able to identify the regions because they made allowance for obesity of the study participants:
differences in obesity might otherwise have masked the effect of genetic variants that influence insulin resistance.

Worldwide, more than 350 million people have type 2 diabetes, and this number is increasing rapidly. People with
diabetes either secrete insufficient amounts of insulin, a hormone that controls blood sugar levels, or are resistant
to its actions.

Previous studies have identified many genes associated with type 2 diabetes and insulin secretion, but little is known
about the genetic basis of insulin resistance. This is surprising, because the heritability of insulin resistance has
clearly been demonstrated in family and twin studies.

"Insulin resistance, diabetes and obesity are intricately linked in networks of
interactions," says Dr Inês Barroso from the Wellcome Trust Sanger Institute. "We know
that insulin resistance has a significant genetic component and we hypothesized that the degree of adiposity might mask
or modify the association between genetic variants and insulin resistance traits. We wanted to see if we might uncover
novel variants if we accounted for the effects of body mass index.

" We found six novel regions associated with insulin resistance that should help us to characterize further the
causes of type 2 diabetes. "

Dr Inês Barroso

"Our approach succeeded: we found six novel regions associated with insulin resistance. These regions should help us to
characterize further the causes of type 2 diabetes."

We know that obesity is a major risk factor for insulin resistance. It is possible that the strong influence of obesity
'masks' the comparatively smaller genetic effects on insulin resistance that remain to be discovered. In addition, the
risk of developing insulin resistance in a person who is genetically susceptible may differ depending on whether or not
they are obese.

The research was carried out by a consortium of scientists affiliated with more than 150 institutions, who examined
almost 100,000 samples. Researchers in the consortium (MAGIC: the Meta-Analyses of Glucose and Insulin-related traits
Consortium) work collaboratively to identify novel genetic regions that influence glucose and insulin levels and other
metabolic traits. It is the scale of this study that allowed the team to look at genetic effects on glucose and insulin
levels across the whole genome: they accounted for differences in obesity levels between study participants while at
the same time testing whether these genetic effects were different in people of different body size.

"Applying this method on a large scale we identified six genetic variants not previously known to
be associated with insulin levels," explains Dr Claudia Langenberg, lead author on the study from the MRC
Epidemiology Unit in Cambridge. "We also found that individuals carrying these risk variants had
higher triglyceride and lower high-density lipoprotein cholesterol levels, linking these different features of insulin
resistance.

"Our findings highlight the importance of taking body weight into consideration when studying the genetic basis of
insulin resistance and its role for type 2 diabetes. The application of our statistical method can be useful for future
genome-wide studies of other diseases that are strongly influenced or vary by known risk factors, such obesity, smoking
or others."

Funding

A full list of funding agencies and acknowledgements can be found at the Nature Genetics website.

Participating Centres

A full list of participating centres can be found at the Nature Genetics website.

The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.

Website

The Wellcome Trust

The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.